A large database study of hospitalization charges and follow-up re-admissions in US lumbar fusion surgeries using a cellular bone allograft (CBA) versus recombinant human bone morphogenetic protein-2 (rhBMP-2)

Lumbar spine disorders are among the most prevalent medical diagnoses across the globe [1] and spinal fusion surgeries are a common and historically successful intervention [2]. Autologous iliac crest bone grafts (ICBG) are traditionally preferred for these procedures due to their presumed potential to provide all three necessary properties for bone fusion (i.e., osteoconductivity, osteoinductivity, and osteogenicity) [3]. However, the supply of such material is limited, and the additional surgical procedure increases operative time, blood loss, risk of infection, and post-operative pain [4]. Additionally, the autograft quality may be limited by patient comorbidities [4]. Thus, alternatives have emerged to meet the need for grafting materials that circumvent the inherent drawbacks of ICBG.

Among these alternatives, recombinant human bone morphogenetic protein-2 with a bovine collagen sponge scaffold (rhBMP-2; marketed as Infuse™ by Medtronic Inc., Memphis, TN), has been widely used since gaining approval by the US Food and Drug Administration in 2002 [5‐7]. Although currently indicated in the spine solely for use in single-level anterior lumbar interbody fusion (ALIF) and single-level oblique lateral interbody fusion (OLIF) surgeries, up to 85% of its use is reported to be off-label [5, 8]. Bone morphogenetic protein-2 is part of a larger family of osteoinductive proteins known to induce mesenchymal stem cells to differentiate into bone-forming cells, such as osteoblasts [5]. However, rhBMP-2 alone is neither osteoconductive nor osteogenic and is thus often used in conjunction with other grafting materials. In spite of serious complications attributed to rhBMP-2 in the spine (e.g., wound complications, increased myelopathy/radiculopathy, and heterotopic ossification) [9, 10], several clinical studies have demonstrated that rhBMP-2 in lumbar fusion surgeries increases fusion rates compared to ICBG, while also decreasing fusion time and refusion rates [11]. However, rhBMP-2 remains relatively expensive [12, 13] and some third-party payers have become increasingly unwilling to reimburse for its prevalent off-label use, leading to downward trends in its overall use from all-time highs in 2009 [7, 14].

Cellular bone allografts (CBAs) are another alternative, which theoretically contain osteoinductive, osteoconductive, and osteogenic properties [15, 16]. In particular, a more recent advanced CBA comprised of viable cryopreserved lineage-committed bone-forming cells (V-CBA; marketed as ViviGen® by LifeNet Health®, Virginia Beach, VA) uniquely emulates the benefits of ICBG without its inherent drawbacks [16‐20]. Unlike rhBMP-2, V-CBA can be used for homologous repair of any bone defect throughout the body [8, 21]. Clinical studies of spinal fusion surgeries using V-CBA have thus far reported successful fusion outcomes [16, 17], and V-CBA is potentially less expensive than rhBMP-2. However, no research to date has compared these two grafts on any level.

Thus, the primary objective of this study was to compare initial procedure and 12-month follow-up hospitalization charges and resource utilization for lumbar fusion surgeries using rhBMP-2 versus V-CBA using data from a large nationwide US healthcare system. The secondary objective was to assess the incidence of potentially relevant re-admissions during the follow-up period, including any subsequent lumbar fusion procedures.

The primary objective of this study was to compare initial procedure and 12-month follow-up hospitalization charges and resource utilization for lumbar fusion surgeries using rhBMP-2 versus V-CBA using data from a large nationwide US healthcare system. The secondary objective was to assess the incidence of potentially relevant re-admissions during the follow-up period, including any subsequent lumbar fusion procedures. The present data showed that hospitalization charges were significantly lower when V-CBA was used in US lumbar fusion surgeries versus rhBMP-2, with $51,130 less in adjusted mean initial procedure charges, and $22,091 less in adjusted mean follow-up hospitalization charges (Fig. 2).

Although the use of rhBMP-2 is almost universally reported to increase hospitalization costs [6, 12, 13, 25‐27], the cause of these large disparities is unknown, as they cannot be explained by direct product costs alone. A definitive answer to this question is beyond the scope of this study; however, an exploration of potential causes is warranted, albeit speculative. The disparity is likely explained by a cluster of smaller contributing factors, including direct product cost, non-cost-effective use of rhBMP-2, and the expense of adjunct products and procedures sometimes used with rhBMP-2, such as demineralized bone matrix or platelet-rich plasma (PRP). This is in contrast to V-CBA, which is similar to autograft in that the use of adjuncts is unnecessary.

Additional costs could also be attributed to operating room time required for preparation of rhBMP-2 (≥ 15 min) versus V-CBA (< 5 min), as well as that required for preparation of rhBMP-2 adjuncts (e.g., spinning/prep of PRP). A study by Hall and colleagues of multi-level instrumented posterolateral fusion (IPLF) surgeries using V-CBA reported a mean operative time of 211.1 (± 87.3) min with an average of 4.1 levels treated [16]. Yet Glassman and colleagues reported a mean operative time of 248 (± 58.5) min with IPLF surgeries using rhBMP-2 (average 1.96 levels treated) and 270 (± 33.6) min in those using ICBG (average 1.98 levels treated) [26]. As noted by Hall, the use of V-CBA thus corresponded with an average of 37- and 59-min faster surgeries than with rhBMP-2 and ICBG, respectively [16], despite the difference in number of levels treated. Such disparities in operative time could potentially contribute to exponential differences in cost.

Another potential contributor may be procedure complexity, as surgeons may default to rhBMP-2 in more complex cases. To this end, the present data could only differentiate between single- and multiple-level surgeries, and multiple-level surgeries have substantially wider variation in costs, particularly with three or more levels of treatment. We hypothesized that such surgeries may have had undue influence on these data, in spite of being treated as covariates in the main analysis. As such, an ad hoc cost analysis was conducted using only charge data from single-level fusion procedures, which involved 86.26% (n = 5683) and 88.74% (n = 8505) of V-CBA and rhBMP-2 patients, respectively (Fig. 3). In theory, single-level cases should be more standardized. Yet, even under these more-aligned conditions, the adjusted mean initial procedure hospitalization charges remained significantly lower in the V-CBA group with $46,556 less charges. These results suggest that procedure complexity does not contribute substantially to the cost disparity.

The difference in initial procedure charges may also be partially influenced by the statistically significant increase of 0.11 days in adjusted mean initial procedure LOS found in the rhBMP-2 group (Table 2). However, the potential influence of this factor on charges was not reflected in the cumulative follow-up LOS, for which a significant mean increase of 0.41 days was observed in the V-CBA group, in spite of the $22,091 cost differential during this period. Notably, the unadjusted LOS range in the V-CBA group was much wider (0–282 days) than in the rhBMP-2 group (0–92 days), which likely contributed to these results and may be related to the significantly higher initial CCI for this group. However, given such small disparities at both time points, it is difficult to attribute any further clinical or practical significance to these results.

Regarding clinical outcomes, our analysis was restricted to hospitalizations within the Premier Healthcare System and, therefore, 12-month follow-up re-admissions may be underestimated. However, it is reasonable to expect that the proportion of patients seeking treatment outside of the Premier Healthcare System was evenly distributed between the groups. It is also important to note that, unlike with the primary cost and LOS analyses, the binary nature of these data prevented control of the confounding baseline variables. Thus, their interpretation requires consideration of the confounding variables and, in particular, the individual Charlson comorbidities.

Accordingly, although the majority of potentially relevant 12-month re-admissions were similar between the groups, significantly higher rates of cardiac complications and pneumonia were observed in the V-CBA group versus the rhBMP-2 group (Table 3). However, although it was not possible to definitively determine relationships between specific comorbidities and follow-up diagnoses within each patient, these differences in follow-up diagnoses corresponded to the significantly higher prevalence of related pre-existing diagnoses in the V-CBA group (Table 1), including cerebrovascular disease, chronic obstructive pulmonary disorder, diabetes with chronic complications, myocardial infarction, and peripheral vascular disease. This trend remained in the ad hoc analysis of single-level treatment only, with only the cardiac complications remaining significant (Table 3). Therefore, the differences in 12-month follow-up re-admissions between V-CBA and rhBMP-2 are expected and align with corresponding differences in initial comorbidities.

The presence of malignancy and metastatic solid tumor in both groups during the initial procedure is worth noting, as these comorbidities are contraindicated with rhBMP-2 [28]. V-CBA can be used in patients with cancer, although it is not recommended when the patient is considered immunocompromised, such as may occur when actively receiving treatment (e.g., chemotherapy or radiation). However, it was not possible to determine if such treatments were received concomitantly in the present data. Further, a follow-up analysis revealed that the presence of these comorbidities did not appear to substantially alter rates of re-admission for either of the V-CBA or rhBMP-2 groups, as only one such patient was re-admitted (from the rhBMP-2 group for urinary tract infection; data not shown).

There were no significant differences in rates of subsequent lumbar fusion procedures between the V-CBA and rhBMP-2 groups for the full cohort. However, these rates were significantly lower in the V-CBA group among patients receiving single-level treatments only (Table 3). The low rate of subsequent lumbar fusion with rhBMP-2 is a frequently cited benefit over ICBG and a principal justification of its cost [11, 13, 27]. As such, the performance of V-CBA in this study is notable, especially in light of the substantially lower average initial hospitalization charges observed for V-CBA patients, and in spite of the higher level of initial comorbidities in this group.

Large database studies have inherent limitations. For instance, the data from the PHD reflect the dollar amount that was charged for patient services, which may not reflect the final cost to the patient or third-party claims paid to the hospital or provider. Those final charges would only be available to the hospitals and are beyond the scope of this study. Further, although this study provides access to high-quality economic and clinical data, some potentially relevant patient and procedure details were unavailable, such as extended medical histories, surgical approaches used, or fusion outcomes. Increased granularity may have helped differentiated factors affecting clinical outcomes or charges. As well, some patients may have received follow-up treatment outside of the Premier Healthcare System, making their data unavailable. Additionally, the grafting material used during the initial procedure was collected as a subjective text string and, in some cases, was not sufficient to definitively determine the material used. Thus, some patients with data relevant to V-CBA or rhBMP-2 may have been inadvertently excluded. Finally, the present data represented economic and clinical information from US hospitals only and thus did not permit characterization for other regions.

The results of this study indicate that use of V-CBA for lumbar fusion surgeries performed in the US may result in substantially lower overall hospitalization charges versus rhBMP-2, with both exhibiting similar rates of 12-month re-admissions and subsequent lumbar fusion procedures.